Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative therapy for many patients with hematologic malignancies and marrow failure. The full potential of HSCT is limited by transplant related complications -particularly acute and chronic GVHD (cGVHD). Traditional means to control GVHD, particularly cGVHD, are only partially effective. Despite excellent control of acute GVHD, 50-70% of patients develop cGVHD. Chronic GVHD is the primary late complication of HSCT. The heterogeneity of manifestations and late onset has led to a situation where research lags behind clinical needs. The importance of cGVHD is increasingly relevant as 1) improvements in HSCT technology allow the use of older donors to transplant older patients, 2) the incidence of cGVHD increased due to greater use of peripheral blood as a stem cell source, and 3) improvements in supportive care result in less nonrelapse mortality and thus more patients alive in the late time periods when cGVHD occurs. This is an opportunity to embark on novel studies to leverage new information on the pathobiology of GVHD. The importance of B cells and regulatory T cells (Treg) is increasingly clear, but there has been little effort to directly manipulate B cell and Treg function in humans. We now know that B cells work with T cells in a coordinated fashion to produce cGVHD. Project 1 includes three Specific Aims (SA) including 5 projects to develop new strategies to prevent and treat GVHD. SA1a is a novel approach to prevent cGVHD in patients without active GVHD using monoclonal anti-CD20 to target the B cell component of cGVHD. In SA1b the goal is to eliminate calineurin inhibitors (CNI) from GVHD prophylaxis. CNI have undesirable intrinsic toxicity, and they inhibit Treg in a counterproductive fashion. By using CNI-free regimens, the expansion of Treg is facilitated to reduce both allo- and autoimmunity, and thus the overall risk of both acute and cGVHD. In SA 2 strategies to prevent a major complication of HSCT, hepatic VOD are assessed. In SA 3, two complementary approaches to treat steroid-resistant cGVHD will be evaluated: 1) by coordinately inhibiting both B and T cells with low dose anti-CD52 monoclonal antibody, and 2) by expansion of Treg with ultra low dose IL-2.